Fentanyl hapten, fentanyl hapten-conjugates, and methods for making and using

Abstract

This disclosure describes a fentanyl hapten, a fentanyl hapten-carrier conjugate, methods of making the fentanyl hapten and the fentanyl hapten-carrier conjugate, and methods of using the fentanyl hapten and the fentanyl hapten-carrier conjugate. The fentanyl hapten-carrier conjugate may be used, for example, as a prophylactic vaccine to counteract toxicity from exposure to fentanyl and its analogues. In some embodiments, the fentanyl hapten-carrier conjugate or a composition including the fentanyl hapten-carrier conjugate may be used in an anti-opioid vaccine.

What is claimed is: 
     
         1 . A fentanyl hapten-carrier conjugate comprising
 a fentanyl hapten comprising   
       
         
           
           
               
               
           
         
       
       and
 an immunogenic carrier, wherein the fentanyl hapten is conjugated to the immunogenic carrier. 
 
     
     
         2 . The fentanyl hapten-carrier conjugate of  claim 1 ,
 wherein the F 1  has a differential scanning calorimetry (DSC) thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 110 degrees Celsius (° C.) to 130° C.;   wherein the F 1  has a DSC thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 175° C. to 185° C.;   wherein the F1 has a decompensation temperature of at least 200° C., at least 225° C., or at least 250° C., as measured by thermogravimetric analysis (TGA); or   wherein the F1 has a haptenation ratio to BSA, of at least 10, at least 15, at least 20; or more than 20; or   a combination thereof.   
     
     
         3 . The fentanyl hapten-carrier conjugate of  claim 1 , wherein the immunogenic carrier comprises a carrier selected from bovine serum albumin (BSA), ovalbumin (OVA), keyhole limpet hemocyanin (KLH); CRM; a liposome, tetanus toxoid (TT); a peptide; macro-, micro-, and nano-particles or combinations thereof; a carbon-based particle; a nanocarrier; a protein of viral, bacterial, or synthetic origin; or another immunogenic component; or a mixture or combination thereof. 
     
     
         4 . The fentanyl hapten-carrier conjugate of  claim 1 , wherein the immunogenic carrier comprises KLH. 
     
     
         5 . The fentanyl hapten-carrier conjugate of  claim 4 , wherein the immunogenic carrier comprises GMP grade subunit KLH (sKLH). 
     
     
         6 . The fentanyl hapten-carrier conjugate of  claim 1 , wherein the immunogenic carrier comprises CRM. 
     
     
         7 . The fentanyl hapten-carrier conjugate of  claim 1 , wherein the fentanyl hapten is conjugated to the immunogenic carrier through carbodiimide chemistry. 
     
     
         8 . A composition comprising the fentanyl hapten-carrier conjugate of  claim 1 . 
     
     
         9 . The composition of  claim 8 , wherein the composition further comprises an adjuvant. 
     
     
         10 . The composition of  claim 9 , wherein the adjuvant comprises an aluminum salt-based adjuvant, complete Freund's adjuvant (CFA), incomplete Freund's adjuvant (IFA), a phytol-based adjuvant, a carbohydrate-based adjuvant, a toll like receptor agonist, a oligomerization domain (NOD)-like receptor (NLR) agonist, a RIG-I-like receptor (RLR) agonist, a C-type lectin receptor (CLR) agonist, degradable nanoparticles, or non-degradable nanoparticles, or combinations thereof. 
     
     
         11 . A method comprising administering the fentanyl hapten-carrier conjugate of  claim 1  to a subject. 
     
     
         12 . The method of  claim 11 , wherein the subject comprises a soldier, a law enforcement professional, a health profession, or a first responder. 
     
     
         13 . The method of  claim 11 , wherein the subject comprises an individual who has been diagnosed with an opioid use disorder or a substance use disorder. 
     
     
         14 . The method of  claim 11 , wherein the subject comprises an individual who has recovered from an opioid use disorder or a substance use disorder. 
     
     
         15 . The method of  claim 11 , wherein the method comprises administering multiple doses of the fentanyl hapten-carrier conjugate to the subject. 
     
     
         16 . The method of  claim 11 , wherein the method comprises administering the fentanyl hapten-carrier conjugate to the subject in combination with an opioid agonist or partial agonist. 
     
     
         17 . The method of  claim 11 , wherein the method comprises administering the fentanyl hapten-carrier conjugate to the subject in combination with an opioid antagonist. 
     
     
         18 . The method of  claim 11 , wherein the method comprises administering the fentanyl hapten-carrier conjugate to the subject in combination with a non-fentanyl opioid or a non-opioid drug hapten-carrier conjugate. 
     
     
         19 . The method of  claim 11 , wherein the subject may be exposed to an opioid or that has been exposed to an opioid or that is suspected of having been exposed to an opioid. 
     
     
         20 . The method of  claim 19 , wherein the opioid comprises fentanyl, sufentanil, acetylfentanyl, and/or carfentanil. 
     
     
         21 . A fentanyl hapten comprising 
       
         
           
           
               
               
           
         
         wherein the F 1  has a differential scanning calorimetry (DSC) thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 110 degrees Celsius (° C.) to 130° C.; 
         wherein the F 1  has a DSC thermogram exhibiting an endothermic event having a melt maxima temperature in a range of 175° C. to 185° C.; 
         wherein the F1 has a decompensation temperature of at least 250° C., as measured by thermogravimetric analysis (TGA); or 
         wherein the F1 has a haptenation ratio to BSA, of at least 10, at least 15, at least 20; or more than 20; or 
         a combination thereof. 
       
     
     
         22 . The fentanyl hapten of  claim 21 , wherein the F1 has a haptenation ratio to BSA of at least 20. 
     
     
         23 . A method of making a fentanyl hapten comprising 
       
         
           
           
               
               
           
         
       
       the method comprising the synthesis shown in the following Scheme: